PROJECT SUMMARY/ABSTRACT There is a fundamental gap in understanding the pathogenesis of ovarian carcinoma. Other than inherited mutations in proven ovarian cancer susceptibility genes, the direct cause for most cases is unknown. The lack of understanding of the initiating events hampers efforts at early detection, prevention, and even targeted therapy of this most lethal gynecologic malignancy. The overall objective of this application is to investigate novel pathways leading to ovarian cancer, and thus enable future investigations in developing prevention and treatment strategies. A novel yet highly plausible central hypothesis for ovarian carcinogenesis is proposed here: ascending infection with some genital tract bacteria leads to inflammation in the fallopian tubes and DNA damage to cells resulting in ovarian cancer. Multiple pieces of evidence support this hypothesis, such as the protective effect of bilateral tubal ligation and oral contraceptives against ovarian cancer, and the increased risks of ovarian cancer associated with endometriosis. However, direct evidence is lacking. Therefore, this hypothesis will be tested by pursuing four specific aims: 1) To determine if the microbiome of normal fallopian tubes is different from patients with a diagnosis of ovarian carcinoma according to specific histology; 2) To determine if the fallopian tube microbiome in patients with endometriosis is different from that of women without endometriosis; 3) To compare the fallopian tube microbiome in patients with BRCA1 mutations who are cancer free with those who have premalignant alterations; and 4) To compare the transcriptomes of normal fallopian tube epithelial cells from the fimbrial ends of ligated tubes with those from patent tubes in age matched controls. The 16S rRNA gene sequencing technology that is well established in Dr. David Fredricks' lab, and a long-standing ovarian cancer and fallopian tube tissue bank that is directed by Dr. Elizabeth Swisher will be utilized in this project. The proposal is innovative because the hypothesis is completely novel and has not been tested before even though it is biologically plausible and supported by previous studies. The proposed research is significant because by collecting direct evidence that associates ovarian cancer to an altered tubal microbiome, it is expected to vertically advance and expand our understanding of the pathogenesis of ovarian cancer and the pathological roles of fallopian tubes. Ultimately, such knowledge has the potential to decrease ovarian cancer mortality through early detection, prevention, or targeted therapy. During the career development award period, the applicant will have ample opportunities of interdisciplinary training in translational research, microbiology, genomics, and cancer biology, which will open a pathway to a productive research career and ultimately to a career goal of improving women's health through scientific discoveries.